LIPID METABOLISM 3

Atherosclerosis - Defenition

It is the process that leads to the narrowing, or a sudden complete occlusion, of the arterial lumen.

  • lipid deposition in the subendothelial layer

ASCVD

  • coronary heart disease stops oxygen from getting to the heart and causes muscles to stop pumping blood around the body

  • stroke

  • peripheral vascular disease (in the leg)

  • renal artery disease will stop waste from leaving the body

PROGRESSION

Material from the blood will fill the RLP area

RLP carries fat and proteins and deposits them in the blood tissue

RLP is the material left off after the body has digested the fatty acids and proteins

Macrophages take up anything that is Foreign in that tissue

foam cells send out signals to get more monocytes to help get rid of these tissues which create more foam cells in that tissues

higher blood pressure because of a narrow pathway.

this will damage the tissue.

angiogenesis - formation of new blood vessels

1) Endothelial Dysfunctional

2) formation of lipid layer within the intima

3) monocytes and smooth muscle cells migrate into the vessel wall to form macrophages

4) Foam cell formation ( Cholesterol as detergent)

5) Degradation of extracellular matrix

Calcification - Calcium build up in Plaques

  • > 5 years after plaque formation

  • The problem is over 40s

  • Arteries stiff, reduced expansion and contraction make it more difficult to treat Atherosclerosis

  • Stent is needed

Normal endothelial Layer have High Kruppel-like factors (KLF2-KLF4) anti-inflammatory control

Dysfunctional endothelium

A) KLF Factors suppressed

B) NFkB Predominates

  • increases expression of cell-adhesion molecules (CAMS)

  • Promotes adhesion of monocytes and T lymphocytes to endothelium

  • Decrease No production = promotes Vasoconstriction

INFLAMMATION

HDL is good cholesterol it takes away the build-up of macrophages from the liver.

Accentuated traditional Risk Factors

  • Dyslipidemia

  • smoking

  • hypertension

  • Physical activity

  • insulin resistance

  • Obesity

AUTOIMMUNE CONDITIONS :

  • Rheumatologic disorders

  • systemic Lupus Erythematosus

  • Risk factors elicit pro-inflammatory cytokines

High Fat diet

Diabetes and LPL deficiency

  • Increase Chylomicrons and VLDL

    VLDL comes out of the liver to pass fats around the body

Hepatic Lipase deficiency (rare)

  • Usually secreted to the blood

  • helps transport HDLs

  • Converts VLDLs and IDLs to LDLs

in the disease

  • decreased secretion of hepatic lipase

  • change lipoprotein quantity

    • Greater risk of developing atherosclerosis of heart disease

LYSOSOMAL ACID LIPASE DEFICIENCY

  • 1:40k to 300k people

  • lysosomal Acid lipase (LIPA gene muatations)

  • Usually: Cholesteryl esters and triglycerides break down in liver lysosome

EXCESS CHOLINE could possibly lead to heart disease

  • Gut bacteria convert excess dietary choline into trimethylamine

  • liver converts trimethylamine to trimethylamine N oxide

Function of Cholesterol

Modulates membrane fluidity

some nerve cells have 25% in PM

The brain contains 25% of the body’s cholesterol

yet less than 2% of the body’s weight

SYMPTOMS can start before the age of 10

  • abdominal pain is often due to inflammation of the pancreas

  • often enlarged liver

  • half-developed fat deposits under the skin

  • High-fat content in the blood

treatment - low-fat diet

it affects over 44 million people. more in the elderly.

HDL

  • Decreases blood vessel deterioration

  • Decreases vascular inflammation

  • Increase No production

    • HDL LIKE PARTICLES + ApoA-I

  • once in the brain, they can inhibit Beta-Amyloid fibrillization

  • Decrease neuroinflammation

AB plaque can build up in the brain and the brain won’t be able to function properly

HDL cant cross the brain barrier

HDL LIKE PARTICALS + ApoE = detrimental effects (damaging the brain barrier)

PARKINSONS

  • alpha presynaptic protein monomer

  • Triacylglycerols (TAGs)

  • there a certain membrane components the APPM will configure with

  • unfolding of Alpha-Synuclein aggregation

Lipid pathway changes in Parkinson’s

  • decreased cholesterol

  • increases eicosanoids

  • increases DAG TAG AND GPI

  • Decreases sphingomyelin

  • Increased

lipid raft slightly elevated part of the membrane

increase LDL receptors

  • increased LDL uptake in the blood and increased cholesterol clearance

Via decreasing cholesterol precursors:

inhibit bile salt reabsorption

  • ingesting a charged resin (E.g. Cholestyramine)

    • Binds bile salts = decrease reabsorption

PCSK9 target LDL receptor for degradation.

Fibrates

  • Agonists of PPRA transcription factor

  • stimulate lipoprotein lipase

    • decreases plasma triglyceride concentration

    • increase in HDL

NIACIN

  • Binds to niacin receptors

  • reduces free fatty acid release from adipose

  • inhibits HDL uptake by the liver

ULTIMATELY

  • raise HDL

  • LOWE LDL

  • Lower triglycerides